Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria

Abstract

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.

Keywords: EPP; X-linked protoporphyria; XLP; consensus; cutaneous porphyria; diagnosis; erythropoietic protoporphyria; evidence-based; guidelines; management; photodermatoses; protoporphyria.

Figure 1.. Molecular Pathophysiology of the Protoporphyrias

The heme biosynthetic pathway requires eight enzymatic steps. Gain-of-function variants in ALAS2 result in X-linked protoporphyria (XLP), and loss-of-functions variants in FECH result in erythropoietic protoporphyria (EPP). In both, metal-free protoporphyrin IX accumulates in erythroblasts, erythrocytes, the plasma, and the biliary system. Metal-free protoporphyrin IX is photosensitive, particularly to visible light in the blue range, and the light-mediated activation of metal-free protoporphyrin IX produces free radicals that damage the surrounding tissues. ALAS2, aminolevulinate synthase 2; FECH, ferrochelatase; ALAD, delta-aminolevulinic acid dehydratase; PBGD, porphobilinogen dehydratase; UROS, uroporphyrinogen III synthase; UROD, uroporphyrinogen III decarboxylase; CPOX, coproporphyrinogen-III oxidase; PPOX, protoporphyrinogen oxidase

Figure 2.

Cutaneous findings in protoporphyria a) Child with extensive edema of the face with erythema and petechiae b) Adult patient with erythema and edema during phototoxic episode, with hypopigmented scars and skin thickening present Of note, in protoporphyria, the skin may have no visible changes during severely painful phototoxic episodes.